The present invention relates in general to antitumor compounds and, in particular to novel compounds of 7-hydroxylucanthone, 7-hydroxyhycanthone, and their derivatives.
It is known that lucanthone (I) and its metabolite, hycanthone (II), possess antitumor activity. ##STR2## where for: (I) R.dbd.CH.sub.3 (lucanthone)
(II) R.dbd.CH.sub.2 OH (hycanthone).
In the National Cancer Institute (NCI) Screening System on P-388 leukemic mice, (I) has a T/C=160 and (II) has a T/C=166 at a dose of about 60 mg/kg. In the NCI screen, a T/C=125 is considered active and T/C greater than 175 is considered to be worthy of further study as a drug of possible future clinical interest.
If leukemic mice are first treated with metabolic inhibitor however, lucanthone is inactive in an antitumor test.
Since hycanthone (II) is a metabolic of lucanthone, it was thought that it might be the active antitumor agent of lucanthone (I). However, when the mice were treated with a metabolic inhibitor and then given hycanthone, the antitumor activity of hycanthone was abolished also.
The NCI screening test is conducted by infecting two groups of white mice with P-388 lymphotcytic leukemia cells.
The first group of mice are held as a control (C) and predictably die after ten days. The remaining group is treated with (T) by a certain dosage of substance suspected ot have antitumor characteristics for a period of 10 days or for a shorter period, for example two or five days. The number of days behond the ten days that members of the test group (T) survive is utilized in a ratio which is multiplied by 100 to obtain the T/C ratio.
Various derivatives which are structurally similar to compounds (I) and (II) have been disclosed in U.S. Pat. No. 3,577,558 to Rosi and No. 2,653,949 to Archer.
The Rosi patent discloses a tricyclic structure similar to the compound (II) with the possibility of substituting one of the hydrogens in the left ring, at positions 5, 6, 7, or 8 with halo, a lower alkyl or lower-alkoxy. Nowhere is it disclosed that the hydrogen at the 5, 6, 7, or 8 position should be substituted by a hydroxy radical nor that the hydroxy radical should specifically at the 7 position. As will become apparent hereinunder, this substitution and positioning of the hydroxy radical produces new and unexpected results with regard to the anti-tumor activity.
The previous Archer patent discloses a ring structure similar to compound (I) with a hydrogen at the 6 position (according to the convention adopted here) substituted by a halo, a lower-alkyl or a lower-alkoxy radical. Here, again, there is no suggestion that a hydrogen of the left ring should be substituted by a hydroxy group nor that that group should be positioned at the 7-carbon position.
The treatment of mice with the metabolic inhibitor has been disclosed in an article entitled "Antibiotics" by E. Hirschberg, Volume III, J. W. Corcoran and F. E. Hahn, Eds., Springer Verlag, Berlin and Heidelberg, 1974, p. 276.
The mechanism by which lucanthone and hycanthone act as antitumor agents has been shown to be through intercalation into the DNA molecule. See E. F. Gale et al, "The Molecular Basis of Antibiotic Action", Wiley, N.Y., 1972 pp. 188 et seq. According to this mechanism the lucanthone or hycanthone molecules position themselves between the base pairs of the DNA molecule. If in addition chemical bonds are formed between the lucanthone or hycanthone molecules and the DNA, the intercalation becomes more permanent and the DNA replication mechanism is rendered inoperative.